Human immunodeficiency virus (HIV), a cytopathic T-cell lymphotropic retrovirus, is the causative agent of the acquired immunodeficiency syndrome (AIDS). This proposal is directed at obtaining a comprehensive understanding of the molecular mechanisms which regulate HIV gene expression directed by the large terminal repeat (LTR). Features characteristic of some eucaryotic promoters have been ascribed to the HIV LTR: these include a TATA box, an enhancer element, and sites for binding the factor SP1. Evidence for a negative regulatory element has also been presented. The product of a gene encoded by HIV, the transactivator (TAT), has been shown to activate expression from the LTR. In addition, the genes of several DNA viruses (herpes viruses and adenovirus) transactivate expression from the HIV LTR. The mechanisms by which these transactivations occur and the relationship to virus latency remain to be elucidated. Specific Aim 1: Cis-acting elements in the HIV LTR regulating viral gene expression will be defined by analyzing the consequences of specific mutations in the LTR. Specific Aim 2: The mechanism(s) of trans-acting factors regulating LTR-directed viral gene expression will be investigated; interactions of binding factors with specific sequences in the LTR will be directly analyzed. Specific Aim 3: The relationship of regulation of HIV gene expression (directed by the LTR) to viral pathogenesis will be investigated by (1) determining the consequences of mutations in the LTR on virus replication and cytopathology in tissue culture systems, (2) examining natural virus variants which differ in the extent of cytopathic effects in tissue culture cells, and (3) evaluating the affects of HIV infection on expression of cellular genes. Specific Aim 4: The affects of growth conditions and physiology of lymphoid cells on LTR-regulated gene expression will be examined.